The immune system is one of the body’s most important defenders, a bodyguard protecting against infection and disease. As the development of immunotherapies to treat diseases, particularly in cancer treatments, continues to grow, so does the need to better understand the complexities of this system.
A team of metabolism researchers, led by Morgridge Institute investigator Jing Fan, is working to better understand the role of metabolism in immune response. In a paper published online in Nature Metabolism, the Fan Lab highlights how changing metabolism can regulate the different functional states in macrophages over the course of an immune response.
Macrophages are just one of the cells in the immune system, which also includes T-cells and neutrophils, among others.
“Immune cells are made to respond to a constantly changing environment,” Fan says. “When you get an infection or have an injury, they are designed to quickly respond and do all these things to kill the pathogen and promote healing. Metabolism is a great part of this mechanism and just a fascinating, dynamic system.”
The immune system requires a delicate balance and has to be very precisely controlled. Too little response and the pathogens won’t be defeated; too much of a response and the body attacks its own cells and damages tissues.
Every immune cell is activated by different stimulants, each stimulation spurs its own dynamic response, and immune cells also communicate with and are influenced by each other, which adds another layer of complexity.
“The whole immunometabolism field is young, and when you talk about gaps in knowledge, there’s a lot of them,” Fan says. “For example, how does metabolism change and how does that couple to immune cell functions? When different cells respond to the same signal, do they do the same things?”
Gretchen Seim, a graduate student at Morgridge and lead author on the paper, says the biggest takeaway from this study is that metabolic response of these immune cells is dynamic, so studying the process over time is important.
“It’s more dynamic and complicated than previously thought, and if you study its change over time, you can find new insights into how metabolism is supporting function,” Seim says. “It’s not a binary, on or off state, and looking at only one time point is really insufficient to capture the complexity of what’s going on, not just in metabolism, but across the board.”
Fan says one way to think about exploring metabolic pathways is to imagine mapping a city and its traffic flow consisting of various modes of transportation.
“Some people in this field make the map, and are filling in the gaps,” Fan says. “We measure the traffic, the flow of highways and examine how these pathways are regulated and controlled.”
In the Nature Metabolism paper, the Fan Lab zoomed in on the map to look at one interesting pathway activated in macrophages by these stimulants. The next steps would include examining it even closer until all of its various dynamic parts are better defined.
“The more you know about where those particular regulation points are, the better we can find ways to alter them, to change the flow and ultimately the function of the cells in diseases where the immune system is not behaving in the way that we want it to,” Seim says.
A shift in research focus
Jing Fan began her research career with an emphasis on investigating cancer metabolism, which gradually led her to exploring immune metabolism.
Fan’s background was in tumor or cancer metabolism, which involved looking at not just the tumor itself, but the tumor microenvironment and all the non-cancer cells that are involved with it. Macrophages happen to be one of the most abundant non-cancer cell within a tumor environment.
“That’s one fun thing about science, right? You think you were going to study one thing, and it turns into a lot of different, fun questions.”Jing Fan
“The original plan was to study the macrophage metabolism, study cancer, and then study them interacting,” Seim says. “But the macrophages are so exciting by themselves that we continued to pursue that direction.”
“That’s one fun thing about science, right? You think you were going to study one thing, and it turns into a lot of different, fun questions,” Fan says.
The macrophage work is only one part of the Fan Lab’s research in immunometabolism. Through a variety of studies, they’re investigating the mechanisms by which the specific changes in metabolic state can affect cell function, signal, physiology and survival.
Fan says she had to think hard about how to make a successful transition to a new scientific focus, particularly as a researcher early in her career.
“At Morgridge, we speak of pursuing fearless science, and changing fields is not easy,” says Fan. “It’s been very rewarding and exciting, but with excitement there’s an element of risk. This environment [at Morgridge] is great in that I have the flexibility to chase after a research direction that is impactful and could be very fruitful.”